The v-Ha-ras transgenic TG.AC mouse behaves as a genetically initiated model for skin tumorigenesis (Leder et al. 1990). Earlier work in our lab has demonstrated that the initiation of transgene expression in Tg.AC mouse is a critical event for skin tumorigenesis (Hansen and Tennant, 1994a). The sensitivity of the Tg.AC to skin tumorigenesis makes this mouse a potential model for investigating the role other genes that are expressed in the follicular epidermis may have in the development of skin neoplasias. To study this, several experiments are currently being conducted in which progeny resulting from breeding the Tg.AC to various knockout mice (i.e., bcl-2, TGF-alpha, and COX) are subjected to repeated applications of TPA to determine the effect on skin tumor susceptibility. Experiments conducted by Hansen, et. al. (1996, manuscript in preparation) demonstrated the validity of this approach in that it was found that 1) the v-Ha-ras allele partially overcame the tumor resistant phenotype of the C57Bl/6 background, and 2) that the agouti gene does play a role in follicle-derived papillomagenesis in the Tg.AC mouse. Preliminary results from the bcl-2 knockout cross with Tg.AC indicate that low doses of TPA (i.e., 1.25 ug applied twice weekly for 10 weeks) results in fewer papillomas in mice carrying the knockout allele, but at higher doses (i.e., 2.5 ug twice weekly for 10 weeks) mice carrying the knockout allele have more papillomas, suggesting a compensatory mechanism. Data from Tg.AC crossed with a TGF-alpha knockout are indicating that TGF-alpha is not required for induction of papillomagenesis in the Tg.AC. Another potential use for the Tg.AC was suggested by Hansen and Tennant (1994b), where transgene expression was localized to the putative stem cell region of the hair follicle, which would allow trangene expression to be used as a marker to select out a susceptible population of cells. Methods are currently being developed for the separation and characterization of transgene expressing cells from follicular and interfollicular epithelium.